HDAC6 Inhibition for Charcot-Marie-Tooth Disease and ALS

Mechanistic description

HDAC6 deacetylates α-tubulin and regulates cytoskeletal dynamics. HDAC6 overexpression causes axonal transport defects. Selective HDAC6 inhibition restores acetylated tubulin levels, improves axonal transport, and delays disease progression in CMT2A and SOD1 mouse models.

Mechanism / pathway

HDAC6
→
neurodegeneration

Evidence for (4)

HDAC6 inhibition improves axonal transport in CMT2A mice

PMID:20354152
Tubastatin A (HDAC6i) extends survival in SOD1 mice by ~7%

PMID:25324005
HDAC6 knockout mice are phenotypically normal with no major toxicity

PMID:22158827
Ricolinostat (ACY-1215) showed acceptable safety in Phase I/II cancer trials

PMID:clinical

Evidence against (4)

SOD1-G93A mouse is a discredited model with massive overexpression artifact

PMID:27635852
α-tubulin acetylation doesn't always correlate with kinesin/dynein velocity

PMID:20392739
HDAC6-null mice show no axonal transport defects despite complete loss

PMID:22158827
Target promiscuity: HDAC6 affects HSP90, cortactin, tau beyond tubulin

PMID:review

Evidence matrix

4 supporting 4 contradicting

50% supporting

Supporting

HDAC6 inhibition improves axonal transport in CMT2A mice PMID:20354152
Tubastatin A (HDAC6i) extends survival in SOD1 mice by ~7% PMID:25324005
HDAC6 knockout mice are phenotypically normal with no major toxicity PMID:22158827
Ricolinostat (ACY-1215) showed acceptable safety in Phase I/II cancer trials PMID:clinical

Contradicting

SOD1-G93A mouse is a discredited model with massive overexpression artifact PMID:27635852
α-tubulin acetylation doesn't always correlate with kinesin/dynein velocity PMID:20392739
HDAC6-null mice show no axonal transport defects despite complete loss PMID:22158827
Target promiscuity: HDAC6 affects HSP90, cortactin, tau beyond tubulin PMID:review

Cite this hypothesis

Citation

envelope-repair (2026). HDAC6 Inhibition for Charcot-Marie-Tooth Disease and ALS. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-3fcd326bc1

BibTeX

@misc{scidex_hypothesis_h3fcd326,
  title        = {HDAC6 Inhibition for Charcot-Marie-Tooth Disease and ALS},
  author       = {envelope-repair},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-3fcd326bc1},
  note         = {SciDEX artifact hypothesis:h-3fcd326bc1}
}